Abstract The INSPIRE-ASP Trial (INtelligent Stewardship Prompts to Improve Real-time Empiric Antibiotic Selection for Patients) for Abdominal and Skin and Soft Tissue Infections The INSPIRE-ASP Trial (INtelligent Stewardship Prompts to Improve Real-time Empiric Antibiotic Selection for Patients) for Abdominal and Skin and Soft Tissue Infections is a cluster-randomized trial to improve judicious antibiotic prescribing for non-critically ill hospitalized patients with abdominal infections or skin and soft tissue infections. Currently, over half of non-critically ill patients with one of these infections receive extended-spectrum antibiotics when less than 5% have an antibiotic-resistant pathogen. The goal of this trial is to advise physicians to prescribe standard- vs extended spectrum empiric antibiotics based on an algorithm that estimates each patient?s personalized probability of having an antibiotic-resistant infection. This personalized probability is based upon routinely-collected patient information in the electronic health record and local prevalence of resistant organisms in abdominal or skin and soft tissue infections. This trial will compare routine care under hospital-based antibiotic stewardship programs to the enhanced program using the predictive algorithm plus audit and feedback to reduce unnecessary empiric prescribing of extended-spectrum antibiotics. In our first aim, we will develop disease-specific prediction algorithms for abdominal infections and for skin and soft tissue infections. In our second aim, this predictive algorithm will be integrated into the computerized provider order entry (CPOE) system to prompt physicians when selected antibiotics are discordant with the estimated need for that antibiotic. Physicians will be prompted to use standard-spectrum antibiotics when the risk of an antibiotic-resistant infection is low. Sixty hospitals will be randomized to either routine care or the CPOE prompt intervention plus feedback. This 18-month study will evaluate ~53,000 patients with abdominal infections and ~37,000 patients with skin and soft tissue infections. This trial will evaluate the ability of a real-time risk calculator plus audit and feedback to reduce unnecessary extended-spectrum antibiotics while maintaining good clinical outcomes as measured by length- of-stay and transfer to an intensive care unit. These methods will be readily applicable to other electronic health record prescribing systems.